Hexahydropyrrolobenzodiazepines

ABSTRACT

1,2,4,5,6,7 - HEXAHYDROPYRROLO(3,2,1-JK)(1,4)BENZODIAZEPINES, 1,2,4,6,7 - HEXAHYDROPYRROLO(1,2,3-EF)(1,5) BENZODIAZEPHINES, PROCESES FOR PREPARING THE SAME AND INTERMEDIATES USED TO PREPARE SAID BENZODIAZEPINES. THE BENZODIAZEPINES HAVE CENTRAL NERVOUS SYSTEM SITIMULANT AND DEPRESSANT ACTIVITY.

United States Patent Oflice 3,642,822 HEXAHYDROPYRROLOBENZODIAZEPINESJackson B. Hester, Ir., Portage, Mieh., assignor to The Upjohn Company,Kalamazoo, Mich.

No Drawing. Filed Nov. 3, 1969, Ser. No. 873,720 Int. Cl. C07d 53/02 US.Cl. 260-326.!) 8 Claims ABSTRACT OF THE DISCLOSURE 1,2,4,S,6,7Hexahydropyrrolo[3,2,1-jk][1,4]benzodiazepines, 1,2,4,5,6,7hexahydropyrrolo[1,2,3-ef][1,5] benzodiazepines, processes for preparingthe same and intermediates used to prepare said benzodia'ziepines. Thebenzodiazepines have central nervous system stimulant and depressantactivity.

BRIEF SUMMARY OF THE INVENTION wherein R is selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, isopropyl, methoxy,ethoxy, propoxy, isopropoxy, and halogen.

The term novel compounds of this invention, as used throughout thespecification embraces the compounds represented by Formulae I and IIabove and the acid addition salts of said compounds.

The term halogen is inclusive of chlorine, bromine and fluorine.

The compounds of Formula I can be prepared by reducting thecorresponding 1,2,4,5 tetrahydropyrrolo [3,2,1-jk][1,4]-benzodiazepin7(6H) ones (III) and the compounds of Formula II can be prepared byreducing the corresponding l,2,4,S-tetrahydropyrrolo[1,2,3-ef][1,5]benzodiazepin-6(7H)-ones (IV). The reduction is illustrated by thefollowing equations.

wherein R is the same as above.

3,642,822 Patented Feb. 15, 1972 DETAILED DESCRIPTION In the processesillustrated by Equations A and B, the reduction is carried out witheither lithium aluminum hydride or diborane in the presence of an inertsolvent such as ether, tetrahydrofuran, dioxane or diglyme at atemperature of 0 to C. and a reaction time of from 1 to 18 hours. t

The 1,2,4,5 tetrahydropyrrolo[3,2,1-jk][l,4]benzodiazepin-7(6H)-ones(III) and the 1,2,4,5-tetrahydropyrrolo[1,2,3-ef][1,5]benzodiazepin6(7I-I)-ones (IV), utilized in processes A and B respectively areprepared by processes illustrated by the following equations:

@3 Step 1 Step2 R H R v CH OH CN Step 3 Step 4 i N N R & R HzCHzCOOH VII0 VIII R N R N o HN III IV wherein R is the same as above.

Step 1 involves reacting the appropriate indoline (V) with acrylonitrileto form a l-indolinepropionitrile (VI). In step 2, thel-indolinepropionitrile is converted to the correspondingl-indolinepropionic acid (VII). Step 3 involves heating thel-indolinepropionc acid with polyphosphoric acid to form a l,2,4,5tetrahydro 6I-I-pyrrolo- [3,2,1-ij1quinolin-6-one (VIII). The conditionsutilized in these three steps are described in considerable detail inRapoport et al., J. Org. Chem. 23, 248 (1958).

In step 4, the l,2,4,5-tetrahydro-6H-pyrrolo[3,2,1-ij1- q-uinolin-6-one(VIII) is reacted with sodium azide in the presence of polyphosphoricacid to form a mixture of l,2,4,5tetrahydropyrrolo[3,2,l-jk][1,41benzodiazepin- 7(6I-I)-one (III) and1,2,4,5-tetrahydropyrrolo[1,2,3-ef1- [l,5]benzodiazepin 6(7I-l) one(IV). These compounds are readily separated by conventional procedures,e.g. chromatography or fractional crystallization.

The preferred reaction temperature range is 50 to 60 C., however, higheror lower temperatures may be utilized if desired. The molar ratio of theketone (VIII) to sodium azide is preferably 1:1 to 1:2 and the reactiontime is from 1 to 5 hours.

The 9 substituted-1,2,4,5-tetrahydropyrrolo[1,2,3-ef1-[l,5]benzodiazepin-6(7H)-ones of Formula We. can also be prepared by theprocess illustrated by the following equation.

| H-HCl NH: EN

wherein R is methyl, ethyl, propyl, isopropyl and halogen. This processis preferably conducted at a temperature range of 80-110 C.; however,higher or lower temperat-ures may be used. The molar ratio of theindoline hydrochloride (IX) to acrylic acid can be 1:1 to 1:2 and thereaction time is from 0.5 to 2 hours.

The indolines (V) utilized in process C to prepare the 1,2,4,5tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin- 7(6H)-ones (HI) and the1,2,4,5-tetrahydropyrrolo[1,2,3- ef] [1,5 ]benzodiazepin-6(7H)-ones (IV)are readily available either from commercial sources or from methodsthat are well known in the art. For example, a method for preparingindolines of the type used in method C is described in R. Ikan et al.,Israel]. Chem. 2, 37 (1964).

The 7-aminoindoline hydrochlorides (IX) utilized in process D can beprepared by a method illustrated by the following equations.

Ae O HNO; Step 1 Step 2 N N H Va X 1101 Zu/NnOH ste 3 Step 4 N \N l HN01 0 N XI XII R H01 R1 N N H l H NH, NH;

XIII IX wherein R is the same as above.

In step 1, the appropriate indoline (Va) is mixed with acetic anhydrideto form the corresponding l-acetylindoline (X).

In step 2, the l-acetylindoline (X) is dissolved in an aceticanhydride-acetic acid mixture, cooled to 10-15" C. and then treateddropwise with a solution of fuming nitric acid in acetic acid. Themixture is kept at 10-15" C. for an additional 2 hours and then pouredinto water. The product, a 1-acety1-7-nitroindoline (XI), is recoveredby conventional procedures such as filtration.

In step 3, the 1-acetyl-7-nitroindoline (XI) is heated with an acid,e.g. a mixture of 6 N hydrochloric acid and methanol for l to 8 hours toform the 7-nitroindoline XII).

( In step 4, a mixture of the 7-nitroindoline (XII) and 20% aqueoussodium hydroxide is treated portionwise with zinc at reflux temperature.After the addition, the mixture is refluxed an additional hour to yieldthe 7- aminoindoline (XIII). The 7-aminoindo1ine is then neutralizedwith hydrogen chloride to form the corresponding 7-aminoindolinehydrochloride (IX).

The acid addition salts of the invention comprise the salts of the basiccompounds of Formulae I, H, III and IV above with pharmacologicallyacceptable acids such as sulfuric, hydrochloric, nitric, phosphoric,lactic, benzoic, methanesulfonic, p-toluene-sulfonic, salicylic, acetic,propionic, maleic, malic tartaric, citric, cyclohexanesulfamic,succinic, nicotinic, ascorbic acids and the like.

The novel compounds of this invention having the Formulae I and I Iexhibit a broad range of central nervous system activity in animals,including mammals. For example, 1,2,4,5,6,7 hexahydropyrrolo[3,2,l jk][1,4] benzodiazepine, 9 chloro-1,2,4,5,6,7-hexahydropyrrolo- [3,2,1jk][1,4]benzodiazepine hydrochloride and 9- chloro 1,2,4,5,6,7hexahydropyrrolo[1,2,3-ef] [1,5]- benzodiazepine are nicotineantagonists when administered intraperitoneally to mice at dosages of 13to 16 mg./ kg.

The compound 1,2,4,5,6,7 hexahydropyrrolo[3,2,1-jk] [1,4]benzodiazepineacts as a stimulant when administered to rats intraperitoneally atdosages of 6 to 10 mg./ kg. and the compound9-chloro-1,2,4,5,6,7-hexahydropyrrolo[3,2,l-jk][1,4]-benzodiazepinehydrochloride acts as a stimulant when administered intraperitoneally tomice in dosages of 10 to 30 mg./kg. The latter compound also exhibitsanorexigenic activity when mixed with food and administered orally tomice at dosages of 28 to 325 mg./ kg. during 24 hours.

The compound 9 chloro-1,2,4,5,6,7-hexahydropyrrolo[1,2,3-ef][l,5]benzodiazepine also exhibits sedative activity in micewhen administered intraperitoneally in dosages of to 200 mg./kg.

The compound 1,2,4,5,6,7 hexahydropyrrolo[l,2,3-ef] [1,5]-benzodiazepine dihydrochloride acts as an acute hypotensive' agentwhen administered orally to rats in a dosage of 50 mg./kg.

The intermediates illustrated by Formulae III and IV also exhibitpharmacological activity. For example, 9- chloro l,2,4,5tetrahydropyrrolo[1,2,3-ef][l,5]benzodiazepin-6(7H)-one acts as anicotine antagonist when administered intraperitoneally to mice indosages of 36 to 50 mg./kg.

Some of the compounds exhibit antidiabetic activity. Illustratively, thecompound 1,2,4,5,6,7 hexahydropyrrolo[1,2,3-ef][1,5]benzodiazepinedihydrochloride shows antidiabetic activity when administeredintraperitoneally to mice in a dosage of 100 mg./kg.

For purposes of administration to birds and to mammals, includinganimals of economic value such as horses, cattle, sheep, pigs, mice,rats, rabbits and the like, the novel compounds of the invention can becombined with solid or liquid pharmaceutical carriers and formulated inthe form of tablets, powder packets, capsules and the like solid dosageforms, using starch and like excipients, or

dissolved in suitable solvents or vehicles for oral or I,2,4,5Ietrahydr0pyrr0l0[3,2,1 jk] [I,4]benz0diazepin- 7 (6H )-one and 1,2,4,5tetrahydropyrrolo[1,2,3-ef]- [1,5] benzodiazepin-ti- (7H) -one (a)Mixture of l,2,4,5-tetrahydropyrrolo[3,2,1-jk] [1, 4]benzodiazepin-7(6H)-one and 1,2,4,5-tetrahydropyrrolo[ 1,2,3-ef][1,51-benzodiazepin 6(7H) one.-A stirring mixture of 15.0 g. (0.0867mole) of 1,2,4,5-tetrahydro-(6H)-pyrrolo[3,2,1-ij]quinoline-6-one and450 g. of polyphosphoric acid is warmed under nitrogen to 50 C. andtreated over a period of one hour with 7.35 g. (0.113 mole) of sodiumazide. The reaction mixture is stirred an additional 3.5 hours at 50 C.and then poured into 4 l. of ice water. The resulting mixture is stirreduntil solution is obtained. The solution is made alkaline with 50%aqueous sodium hydroxide and extracted with chloroform. The chloroformextract is washed with water, dried over anhydrous potassium carbonateand concentrated under reducedpressure to yield a mixture of1,2,4,5-tetra- 'hydropy'rro'lo [3,2,1-jk][1,4] benzodiazepin-7(6H)-oneand 1,2,4,5 tetrahydropyrrolo[1,2,3-ef][1,5] benzodiazepin-6(7H)-one.

(b) 1,2,4,5 tetrahydropyrrolo[1,2,3-ef][1,5]benzodiazepin-6(7H)-one.-Theresidue prepared in part (a) is chromatographed on 800 g. of silica gel(elution with 15% methanol-85% ethyl acetate) and the eluate iscollected in 100-ml. fractions. Fractions 15-23 are combined and thenrecrystallized successively from ethyl acetate-Skellysolve B hexanes andmethylene chloride-ethyl acetate to yield 1,2,4,5tetrahydropyrrolo[1,2,3 ef][1,5]benzodiazepin-6(7H)-one, melting point163l64 C.

Analysis.Calcd. for C H N O (percent): C, 70.18; H, 6.43; N, 14.88.Found (percent): C, 69.95; H, 6.67; N, 14.80.

(c) 1,2,4,5tetrahydropyrrolo[3,2,1-jk][l,4]benzodiazepin-7(6H)-one.Fractions 27-50eluted during the chromatography in part (b) above are combined andrecrystallized twice from ethyl acetate to yieldl,2,4,5-tetrahydropyrro1o[3,2,1-jk][1,4]benzodiazepin 7(6H) one, meltingpoint 151-152.5 C.

AnaIysis.--Calcd. for C H N O (percent): C, 70.18; H, 6.43; N, 14.88.Found (percent): C, 70.31; H, 6.39; N, 15.08.

EXAMPLE 2 1,2,4,5,6,7-hexahydrpyrrolo[3,2,1-jk] [1,4] benzodiazepine Asolution of 188 g. (0.01 mole) of1,2,4,5-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-7(6H)-one in 100ml. of dry tetrahydrofuran is added under nitrogen to an ice-cold,stirred suspension of lithium aluminum hydride (1.88 g.) in 100 ml. oftetrahydrofurau. The resulting mixture is refluxed for 18 hours, cooledin an ice bath and treated successively with 1.88 ml. of water, 1.88 ml.of aqueous sodium hydroxide and 5.64 ml. of water. The mixture isfiltered and the filtrate collected and concentrated in vacuo. Theresidue is recrystallized twice from ethyl acetate-Skellysolve B hexaneto give 1,2,4,5,6,7-hexahydropyrrolo[3,2,1-jk][1,4]benzodiazepine,melting point 67-68 C.

AnaIysis.Calcd. for C H N (percent): C, 75.82;

H, 8.19; N, 16.08. Found (percent): C, 75.50; H, 8.15; N,

EXAMPLE 3 1,2,4,5,6,7-hexahydr0pyrr0l0[1,2,3-ef] [1,5]- benzodia'zepinand dihydrochloride thereof A solution of 1.74 g. (0.00925 mole) of1.2,4,5-tetrahydropyrrolo[1,2,3-ef] [1,5]benz0diazepin-6(7H) one in 50ml. of dry tetrahydrofuran is added, under nitrogen, to a stirredice-cold suspension of 1.74 g. of lithium aluminum hydride in 150 ml. oftetrahydrofuran. The resulting mixture is refluxed for 18 hours, cooledin an ice bath and treated succesively with 1.74 ml. of water, 1.74 ml.of 15 aqueous sodium hydroxide and 5.22 ml. of water. The solid whichresults is collected by filtration, and the filtrate is concentratedunder reduced pressure. A solution of the residue in ethyl acetate isacidified with methanolic hydrogen chloride, and the resulting solid iscollected by filtration and dried. The solid is then recrystallized frommethanolic hydrogen chloride to yield 1,2,4,

5,6,7 hexahydropyrrolo[1,2,3 ef][1,5]benzodiazepine dihydrochloride,melting point 22723l C.

Analysis.Calcd. for C H N -2HCl (percent): C, 53.45; H, 6.53; C1, 28.69;N, 11.34. Found (percent): C, 53.67; H, 6.40; Cl, 28.26; N, 11.35.

The free base is prepared by basifying the dihydrochloride with aqueoussodium hydroxide, extracting with ether, and evaporating the extract todryness.

EXAMPLE 4 9-chl0r0 1,2,4,5 tetrahydropyrrolo[3,2,1ik][1,4]benz0diazepin-7 (6H )-one and 9-chloro-I ,2.4,5-tetrahydr0-pyrrolo[1 ,2,3-ef] [I ,5 1benz0diazepin-6 (7H) -one (a) Mixture of9-chloro-1,2,4,5-tetrahydropyrrolo[3,2, 1 jk] [l,4]benz0diazepin 7(6H)one and 9 chloro- 1,2,4,5 tetrahydropyrrolo[1,2,3 ef][1,5]benzodiazepin- 6(7H)-one.--A stirred mixture of 4.15 g. (0.02 mole)of 8 chloro 1,2,4,5 tetrahydro (6H)-pyrrolo[3,2,l-ij]- quinolin-6-oneand g. of polyphosphoric acid is heated under nitrogen to 50-60 C. andtreated portionwise with 1.69 g. (0.026 mole) of sodium azide over aperiod of 1 hour. The mixture is kept at a temperature of 5060 C. for anadditional 4 hours and then poured into ice water. The resultingsolution is rendered alkaline with 50% aqueous sodium hydroxide andextracted several time with chloroform. The combined extract is washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure toyield a mixture of 9-chloro-1,2,4,5- tetrahydropyrrolo[3,2,l jk] [1,4]benzodiazepin-7 (6H)- one and 9 chloro 1,2,4,5tetrahydropyrrolo[1,2,3-ef1- 1,5 benzodiazepin-6 (7H) -one.

Using the procedure described in Example 4, part (a), but replacing 8chloro 1,2,4,5-tetrahydro-(6H) -pyrrolo- [3,2,1-ijlquinolin-6-one by theappropriately substituted 1,2,4,5 tetrahydro (6H)pyrrolo[3,2,1-ii]-quinolin-6- one is productive of a mixture of thecorresponding 1,2,4, 5 tetrahydropyrrolo[3,2,1-jk-] [1,4]benzodiazepin-7(6H), one and1,2,4,5-tetrahydropyrrolo[1,2,3-ef][1,5]benzodiazepin-6(7H)-one.

(b) 9 chloro 1,2,4,5 -tetrahydropyrrolo[3,2,1-jk]-[1,4]benzodiazepin-7(-6H)-one.-The above mixture of 9chloro-1,2,4,5-tetrahydropyrrolo[3,2,1-jk][1,4] benzodiazepin-7 (6H)-oneand 9-ch1oro-1,2,4,5-tetrahydropyrrolo-[l,2,3-ef][1,5]benzodiazepin-6(7H)-one is dissolved in methanol-ethylacetate (decolorizing charcoal treatment). The solution is filtered andcooled and the solid that precipitates is separated by filtration. Thesolid is then recrystallized from methylene chloride-ethyl acetate toyield 9 chloro 1,2,4,5-tetrahydropyrrolo[3,2,1-jk] [1,4]-benzodiazepin-7(6H)-one, melting point 201.5-202" C.

Analysis.Calcd. for C H ClN O (percent): C, 59.33; H, 4.98; Cl, 15.92;N, 12.58. Found (percent): C, 58.97; H, 5.07; Cl, 16.08; N, 12.09.

(c) 9 chloro 1,2,4,5 tetrahydropyrrolo[1,2,3 -ef]-[1,5]benzodiazepin-6(7H)-one.The filtrate from the methanol-ethylacetate recrystallization described in Example 4, part (b) isconcentrated and chromatographed on g. of silica gel with 5%methanol-95% ethyl acetate; 50-ml. fractions are collected. Fractions610 are collected and crystallized from ethyl acetate to give 0.249 g.of crude product. This crude product is recrystallized from a mixture ofethyl acetate and Skellysolve B hexanes to yield 9-chloro 1,2,4,5tetrahydropyrrolo- [1,2,3-ef][1,5]benzodiazepin 6(7H) one, melting point169.5- C.

Analysis.-Calcd. for C H ClN O (percent): C, 59.33; H, 4.98; Cl, 15.92;N, 12.58. Found (percent): C, 59.65; H, 4.98; Cl, 16.06; N, 12.38.

Further elution of the column with 10% methanol-90% ethyl acetate yields9-chloro-1,2,4,5-tetrahydropyrrolo- [3,2,1 jk] 1,4]benzodiazepin7(6H)-one, identical with the product of part (b) above.

7 EXAMPLE 9-chloro-1,2,4,5,6,7-hexahydropyrrol0[3,2,1-jk] [1,4]benzodiazepine and hydrochloride thereof A solution of 1.0 g. (0.0045mole) of 9-chloro-1,2,4,5- tetrahydropyrrolo[3,2,l jk][l,4]benzodiazepin 7(6l-l)- one in 100 ml. of tetrahydrofuran is addedunder nitrogen to a stirred, refluxing suspension of 1.0 g. of lithiumaluminum hydride in 100 ml. of tetrahydrofuran. The resulting mixture isrefluxed for 18 hours, cooled in an ice bath and treated successivelywith 1.0 ml. of water, 1.0 ml. of 15% aqueous sodium hydroxide and 3.0ml. of water. The solid is collected by filtration and the filtrate isconcentrated under reduced pressure. An ethyl acetate solution of theresidue is acidified with methanolic hydrogen chloride and the resultingsalt is crystallized from methanol-ethyl acetate to yield 0.935 g. ofcrude product. The crude product is recrystallized from methanol-ethylacetate to give 9-chloro-1,2,4,5,6,7hexahydropyrrolo[3,2,1-jk][l,4]benzodiazepine hydrochloride, melting point 281 C. (dec.).

Analysis.-Calcd. for C H ClN -HCl (percent): C, 53.89; H, 5.76; CI,28.93; N, 11.43. Found (percent): C, 54.05; H, 5.78; Cl, 28.97; N,11.27.

The free base is prepared by basifying the hydrochloride with aqueoussodium hydroxide, extracting with ether, and evaporating the extract todryness.

Using the procedure described in Example 5, but replacing 9 chloro1,2,4,5 tetrahydropyrrolo[3,2,1 jk]- [1,4]benzodiazepin-7(6H)-one by theappropriately substituted 1,2,4,5-tetrahydropyrrolo[3,2,1 jk][1,4]benzodiazepin-7(6H)-ones is productive of the corresponding1,2,4,5,6,7 hexahydropyrrolo[3,2,l jk] [1,4]benzodiazepines and acidaddition salts thereof. Representative of the 1,2,4,5,6,7hexahydropyrrolo[3,2,l-jk] [1,41benzodiazepines so prepared are8-methyl-, 9-methyl-, 10-methyl-, 8-ethyl-, 9-e'thyl-, 9-propyl-,9-isopropyl-, 8-methoxy-, 9- methoxy-, 10-methoxy-, 9-ethoxy-,8-propoxy-, 9-isopropoxy-, 8-ethoxy-, 8-chloro-, 8-bromo-, 8-fluoro-, 9-fluoro-, 9-bromo-, and10-chloro-1,2,4,5,6,7-hexahydropy-rrolo[3,2,l-jk][l,4]=benzodiazepine.

EXAMPLE 6 9-chl0ro-1,2,4,5,6,7-hexahydropyrrolo- [I ,Z,3-ef][1 ,5]benzodiazepine A solution of 1.0 g. (0.0045 mole) of 9-chloro-1,2,4,5-tetrahydropyrrolo[l,2,3 ef] [1,5]benzodiazepin 6(7H)- one in 100 ml. oftetrahydrofuran is added under nitrogen to a stirred, refluxingsuspension of 1.0 g. of lithium aluminum hydride in 100 ml. oftetrahydrofuran. The resulting mixture is refluxed for 8 hours, cooledin an ice bath and treated successively with 1.0 ml. of water, 1.0 ml.of aqueous sodium hydroxide and 3.0 ml. of water. The solid is collectedby filtration and the filtrate is concentrated under reduced pressure.Chromatography of the residue on silica gel (150 g.) with 30% ethylacetate-70% cyclohexane gives the desired product which is crystallizedfrom ethylacetate-Skellysolve B hexanes to yield 0.681 g. of crudeproduct. This product is recrystallized from ethyl acetate-Skellysolve Bhexanes to yield 9-chloro 1,2,4,5,6,7 hexahydropyrrolo[1,2,3-ef][l,5]benzodiazepine, melting point 77.5-78.5 C.

Analysis.--Calcd. for C H ClN (percent): C, 63.30; H, 6.28; Cl, 16.99;N, 13.43. Found (percent): C, 63.68; H, 6.60; C1, 17.20; N, 13.19.

Using the procedure described in Example 6, but replacing9-chloro-1,2,4,S-tetrahydropyrrolo[ 1,2,3-ef] [1,5benzodiazepin6(7H)-one by the appropriately substituted 1,2,4,5tetrahydropyrrolo[l,2,3 ef] [1,5]benzodiazepin- 6(7H)-ones is productiveof the corresponding 1,2,4,5,6,7- hexahydropyrrolo[ 1,2,3-ef] 1,5]benzodiazepines. Representative of thel,2,4,5,6,7-hexahydropyrrolo[1,2,3-ef] [1,5 ]benzodiazepines so preparedare 8-chloro-, 8-bromo-, 8-fluoro-, 9-bromo-, 10-chloro-, 10-bromo-,9-fiuoro-, 8- methyl-, 8-ethyl-, 8-propyl-, 8-isopropyl-, 9-ethyl-, 9-

8 propyl-, 9-isopropyl-, 9-methyl-, 10-methyl-, 10-ethyl-, 8-methoxy-,9-methoxy-, 10-methoxy-, 9ethoxy-, 9- 'propoxy-, 9-isopropoxy-,8-ethoxy-, and 10-propoxy-l,2,4,5,6,7-hexahydropyrrolo-[1,2,3-ef][1,5]benzodiazepine.

EXAMPLE 7 7-amino-5-cIzlor0i/zd0line hydrochloride A stirred mixture of19.9 g. (0.1 mole) of 5-chloro 7-nitroindoline, 52 ml. of ethanol and 8ml. of 20% aqueous sodium hydroxide is warmed under nitrogen to thereflux temperature and treated, portionwise, with 26 g. of zinc dust atsuch a rate that the mixture refiuxes without external heating. Anadditional 13 ml. of ethanol is added and the mixture is refluxed for 1hour, cooled and filtered. The solid is washed with ether. The combinedfiltrate and washing is treated with 1 g. of sodium hydrosulfite andconcentrated in vacuo. A suspension of the residue in water is extractedwith ether, and the extract is washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous potassium carbonate andconcentrated in vacuo. A solution of the residue in ethanol is cooled inan ice bath and acidified with methanolic hydrogen chloride. Theresulting crystalline solid is collected by filtration and washed withethanol. A small amount of additional solid is obtained by concentratingthe filtrate. The combined solid is recrystallized from ethanol(decolorizing charcoal treatment) to yield 11.449 g. of crude product.The crude product is recrystallized from ethanol to yield7-arnino-5-chloroindoline hydrochloride, melting point 218.5-220 C.(dec.).

A nalysis.Calcd. for C H ClN -HCl (percent): C, 46.85; H, 4.91; CI,34.58; N, 13.66. Found (percent): C, 46.85; H, 4.88; CI, 34.80; N,13.51.

Using the procedure described in Example 7, but replacing5-chloro-7-nitroindoline by the appropriately substituted7-nitroindoline is productive of the corresponding 7-aminoindolinehydrochloride.

- EXAMPLE 8 9-chl0r0-I ,2,4 ,5 detrahydropyrrolofl ,2,3-ef] [1,5benzodiazepirte-6 (7H) -one A mixture of 20.5 g. (0.10 mole) of7-amino-5-chloroindoline hydrochloride, 10.8 g. (0.15 mole) of acrylicacid and 15 ml. of 5.7 N hydrochloric acid is heated on a steam bath for1.5 hours. The mixture goes into solution and then solidfies. The solidis collected, suspended in water and made ammoniacal with concentratedammo nium hydroxide. The resulting mixture is stirred 1 hour andfiltered. The solid is washed with water, dried and recrystallized fromethyl acetate to obtain a 63% yield of9-chloro-1,2,4,5-tetrahydropyrrolo[1,2,3 ef] [1,5]benzodiazepin-6'(7H)-one in three crops: 9.46 g., melting point168-170" C.; 3.15 g., melting point 166.5-168.5 C.; and 1.43 g., meltingpoint 167l68.5 C.

I claim: 7

1. A compound selected from the group consisting of (a) A compoundhaving the formula wherein R is selected from the group consisting ofhydrogen, methyl, ethyl, propyl, isopropyl, methoxy,

ethoxy, propoxy, isopropoxy, and halogen; and

(b) The addition salts with pharmacologically acceptable acids of thecompound of the above formulae.

9 2. A compound of claim 1 having the formula of I. OTHER REFERENCES 3.A compound of claim 2 wherein R is hydrogen. 4. A compound of claim 2wherein R is 9-chloro. 3 jg f gfi g Methods of Orgamc chemlstry 5. Acompound of claim 1 having the formula of II. i 6. A compound of claim 5wherein R i hydrogen. 5 ALEX M AZEL Primary Examiner 7. Thedihydrochloride of the compound of claim 6. 8. A compound of claim 5wherein R is 9-chloro. NARCAVAGE Assmant Exammer References Cited UNITEDSTATES PATENTS 1 252-401; 260-2393 T, 326.11, 326.5 13; 424274 3,466,2979/1969 Sulkowski et al. 260-3261 3,466,298 9/1969 Sulkowski et a1.260-326.1

537 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5,6 l2 ,822 Dated Feb rua U 15, 1 972 Inventol-(g) Jackson B Hester J rIt is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1 l ine 56, for "di borne" read dibora ne Column 1 l i ne 66, for"d i borne read diborane Column 3, l ine 45, for "R1 read R Column 4, li ne 6, for "ma l l c ta rta ri c" read ma l i c, tarta ri c Column 5, li ne 1 For "quinol i ne-" read quinol i n- Column 5, l l ne ll for "188g read 1.88 g Column 5, l ine 51 for "hexane" read hexanes Column 5, l ine 55, for "8.19" read 8.10

Column 8, li ne 68, for "N" read H Signed and sealed this 26th day ofDecember 1972.

(SEAL) Attest:

ROBERT GOTTSCHALK EDWARD M.FLETCHER,JR.

Commissioner of Patents Attesfiing Officer Column 5, l i ne 60, for "benzodiazepi n" read Benzodiazepl ne USCOMM-DC 6037-PO9 9 U 5 GOVERNMENTPRINTING OFFICE: I969 0-366-33l 537 UNETEU STATES PATENT @FFIQEQER'HFiQATE @F QQRREUHN Patent No. 3 ,6 l2 ,822 Dated Feb rua ry 15, 1972 Inventor s Jackson B. Hester, Jr.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, line 56, for diborne read diborane Column 1, line 66, fordiborne read dlborane Column 3, l ine 45, for "R read R Column l, l i ne6, for 'ma l i c ta rtaric" read ma l ic, tartaric Column 5, l i ne 1,for "qulnol i neread quinolin- Column 5, line ll, for 188 read 1 .88 gColumn 5, l ine 51 For '"hexa ne" read hexanes Column 5, l i ne 55, For"8.19" read 8.10 Column 5, l ine 60, for "be nzodiazepi n" readBenzodiazep i ne Column 8, ll ne 68, for 'N' read H Signed and sealedthis 26th day of December 1972.

(SEAL) Attesr:

EDWARD MOFLETCHERJR, ROBERT GOTTSCHALK Abbas-hing; Officer Commissionerof Patents F ORM PO-1050 (10-69) USCOMM-DC 6O376-P69 U.S, GOVERNMENYPRINTING OFFICE: I969 O--3E6-334

